Diabetes has many long term complications, including nephropathy, neuropathy and retinopathy. Retinopathy is primarily a vascular disease brought on by high glucose and resulting damage to vascular tissue with subsequent damage to retinal tissues. Aldose reductase catalyzes the reduction of aldehyde sugars to their alcohol forms; D-glucose is reduced to sorbitol and galactose to galactitol. Under normal conditions the sorbitol pathway plays a minor role in glucose metabolism. However, in hyperglycemia associated with diabetic cells, which have high aldose reductase, glucose and sorbitol levels increase. Due to poor transport out of the cells, the sorbitol accumulates and causes osmotic damage to cells. The lens, retina and peripheral nerves are particularly affected. This has led to the development of drugs, which inhibit aldose reductase activity. Although aldose reductase inhibitors (ARI's) have been used to treat nephropathy and neuropathy, there is no known pharmaceutical treatment for retinopathy. The ineffectiveness of ARI's in treating retinopathy may arise from the insolubility of the drugs in water and the short lifetime (about one half hour in the human body) of these drugs. Current treatment options for retinopathy include surgery and better control of blood glucose, neither of which is completely successful in preventing blindness.
TABLE 1Known ARI's
In addition to the osmotic damage from sorbitol accumulation, the additional flux of glucose through metabolic pathways leads to increased production of diacylglycerol. This leads to cellular changes in the enzyme protein kinase C (PKC). There are various forms of PKC. The PKCβ isoform is abundant in vascular tissue where it plays a role in the maintenance of the normal growth of vascular endothelial cells and pericytes. On the other hand, this isoform is not found in vascular tissue such as lens. In lens and peripheral nerves, a major isoform is PKCγ, an isoform which decreases during diabetes and which functions to control gap junction communication.
Currently, there are five active ARI's reported: Tolrestat, Epalrestat, Ponalrestat, Sorbinil, and Alconil (Table 1). Tolrestat is currently marketed for neuropathy in humans. Currently there are no drugs available for use in dogs.
Because protein kinase C level in diabetes is abnormally high, selective inhibition of protein kinase C-β (PKC-β) has been studied in animals and found to result in normalized retinal blood flow. However, Phase I trials of the drugs used indicate that they may have undesirable side effects. (Aiello,L. et al. Amelioration of Abnormal Retinal Memodynamics by a Protein Kinase C β-Selective Inhibitor (LY33531) in Patients with Diabetes: Results of a Phase I Safety and Pharmacodynanic Clinical Trial. IOVS. 1999, 40, S192; Williamson, J. et al. Ocular and Cerebral Vascular Dysfunction Induced by Diabetes and by LY33531, a β-Selective Inhibitor of Protein Kinase C. IOVS. 1999, 40, S369).
There is a need for drugs that are cell permeable, water soluble and more effective than currently available treatments for the complications of diabetes.